Respiratory syncytial virus is the most common cause of lower respiratory tract disease in young children worldwide. The F glycoprotein of this viru is one of the targets of a protective immune response; however, despite developing anti-F antibodies following natural infection immunity is incomplete and repeated infections still occur. Studies with murine monoclonal antibodies have indicated that the immunodominant response to th F glycoprotein in the mouse is directed to 3 sites involved in neutralization and an additional 3-4 sites that do not mediate virus neutralization. Similar information about the response in humans is not available. In order to investigate the development of a protective humoral immune response in humans we have used two approaches: (1) The ability of post-infection human sera to block binding of biotinylated murine monoclona antibodies in an antigenic site specific blocking assay. (2) Reactivity of post-infection sera in neutralization assays with antigenically distinct RS isolates. The results have indicated that post-infection sera contain relatively low titers of antibodies to neutralization sites on the F glycoprotein; in humans, it appears that the immunodominant responses are t sites that are not involved in neutralization. Similarly, the relative ability of individual sera to neutralize antigenically distinct RSV isolate varied and did not correlate with the ability to neutralize the protypic A2 strain. These data indicate that the human response to the F glycoprotein may produce antibodies of low affinity that do not compete well in this assay or that the dominant anti-F antibody responses are directed to sites not discriminated here. In addition, it appears that the ability to neutralize the prototypic laboratory strain of RSV may not be predictive of protection in vivo; strain specific neutralization responses may be important in determining resistance to infection with wild-type strains of RSV. Current studies are directed to measuring the affinities of anti-F antibodies for a variety of F antigens.